The eMERGE III Clinical Center proposal from Partners HealthCare leverages a large biobank, clinical data in the electronic medical records (EMR) for >4 million participants from the largest integrated health care provider in New England, advanced bioinformatics expertise and state-of-the-art genetic analysis. We propose three aims. (1) Aim 1. Discovery. We will test the hypothesis that common and rare variants from a custom chip including 50,000 loss of function (LoF) alleles will be associated with cardiovascular, neuropsychiatric and immune-mediated phenotypes derived from the EMR. We are currently genotyping 25,000 Partners HealthCare Biobank subjects with a custom chip that includes LoF alleles from 63,000 exomes that we have analyzed. (2) Aim 2. Penetrance and Pleiotropy. We will test the hypothesis that sequencing a set of established genes or loci will allow us to discover additional variation, and define penetrance and pleiotropy using EMR phenotypes. Rare variants in genes selected by the eMERGE network will be studied for penetrance and pleiotropic outcomes by PheWAS and chart review. In addition, we are poised to perform recall-by-genotype studies because all Biobank participants have provided consent for such callback. (3) Aim 3. Implementation. We will test the hypothesis that physicians will alter their surveillance and treatment of patients based upon voluntary return of actionable variants to provide safe and cost-effective benefits to patients. We will screen our entire Biobank population of 25,000 individuals for pathogenic variants in the LDLR gene, the leading genetic cause of premature coronary artery disease, and conduct an exploratory trial in disclosing this information. Biobank participants with pathogenic variants in LDLR will be offered enrollment into a randomized trial, in which their finding will be CLIA-confirmed, and in one arm, this result will be communicated to their physicians through the EMR. Over one year, we will collect the following outcomes through participant surveys and EMR queries: physician visits, laboratory testing, changes in medication prescriptions, LDL levels, medical costs and the number of family members screened and treated as a result of the intervention. We will collaborate with the entire eMERGE III Network to incorporate what we learn from this pilot trial into large-scale implementation protocols for the genes selected by the Network for sequencing. Finally, we will participate in all Network activities to enhance the movement of genetics into clinical practice.